Bryan Kolb

Structural plasticity associated with exposure to drugs of abuse

Persistent changes in behavior and psychological function that occur as a function of experience, such those associated with learning and memory, are thought to be due to the reorganization of synaptic connections (structural plasticity) in relevant brain circuits. Some of the most compelling examples of experience-dependent changes in behavior and psychological function, changes that can last a lifetime, are those that accrue with the development of addictions. However, until recently, there has been almost no research on whether potentially addictive drugs produce forms of structural plasticity similar to those associated with other forms of experience-dependent plasticity. In this paper we summarize evidence that, indeed, exposure to amphetamine, cocaine, nicotine or morphine produces persistent changes in the structure of dendrites and dendritic spines on cells in brain regions involved in incentive motivation and reward (such as the nucleus accumbens), and judgment and the inhibitory control of behavior (such as the prefrontal cortex). It is suggested that structural plasticity associated with exposure to drugs of abuse reflects a reorganization of patterns of synaptic connectivity in these neural systems, a reorganization that alters their operation, thus contributing to some of the persistent sequela associated with drug use--including addiction.

Functions of the frontal cortex of the rat: A comparative review

This review summarizes the anatomical and functional organization of the frontal cortex of the rat in comparison to primates. Lesions of the primary motor or of the prefrontal cortex of both primates and rodents produce a consistent constellation of symptoms that are strikingly similar across species as diverse as rats and humans. Thus, in spite of the tremendous difference in the relative volume of the frontal cortex of mammals, as well as the obvious diversity of behavioral repertoires across mammalian phylogeny, there appears to be a remarkable unity in frontal cortex function across the class mammalia. Hence, motor and prefrontal lesions produce analogous alterations in motor control in rodents and primates even though humans walk upright and have fine control of digit movement and rats walk on all fours and have less dextrous control of distal movements. Similarly, there are analogous changes in behaviors that can be labeled response inhibition, temporal ordering, spatial orientation, social or affective behavior, behavioral spontaneity, olfaction and habituation following prefrontal cortex lesions in both primates and rodents. Finally, it is proposed that the principal function of the prefrontal cortex of mammals is the temporal organization of behavior.

Persistent Structural Modifications in Nucleus Accumbens and Prefrontal Cortex Neurons Produced by Previous Experience with Amphetamine

Experience-dependent changes in behavior are thought to involve structural modifications in the nervous system, especially alterations in patterns of synaptic connectivity. Repeated experience with drugs of abuse can result in very long-lasting changes in behavior, including a persistent hypersensitivity (sensitization) to their psychomotor activating and rewarding effects. It was hypothesized, therefore, that repeated treatment with the psychomotor stimulant drug amphetamine, which produces robust sensitization, would produce structural adaptations in brain regions that mediate its psychomotor activating and rewarding effects. Consistent with this hypothesis, it was found that amphetamine treatment altered the morphology of neurons in the nucleus accumbens and prefrontal cortex. Exposure to amphetamine produced a long-lasting (>1 month) increase in the length of dendrites, in the density of dendritic spines, and in the number of branched spines on the major output cells of the nucleus accumbens, the medium spiny neurons, as indicated by analysis of Golgi-stained material. Amphetamine treatment produced similar effects on the apical (but not basilar) dendrites of layer III pyramidal neurons in the prefrontal cortex. The ability of amphetamine to alter patterns of synaptic connectivity in these structures may contribute to some of the long-term behavioral consequences of repeated amphetamine use, including amphetamine psychosis and addiction.

Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine

Repeated treatment with psychostimulant drugs produces changes in brain and behaviour that far outlast their initial neuropharmacological actions. The nature of persistent drug‐induced neurobehavioural adaptations is of interest because they are thought to contribute to the development of dependence and addiction, and other forms of psychopathology, e.g. amphetamine psychosis. There are many reports that psychostimulants produce biochemical adaptations in brain monoamine systems, especially dopamine systems. The purpose of the present study was to determine if they might also alter the morphology of neurons in brain regions that receive monoaminergic innervation. Rats were given repeated injections of either amphetamine or cocaine, or, to control for general motor activity, allowed access to a running wheel. They were then left undisturbed for 24–25 days before their brains were processed for Golgi–Cox staining. Treatment with either amphetamine or cocaine (but not wheel running experience) increased the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens, and on apical dendrites of layer V pyramidal cells in the prefrontal cortex. Cocaine also increased dendritic branching and spine density on the basilar dendrites of pyramidal cells. In addition, both drugs doubled the incidence of branched spines on medium spiny neurons. It is suggested that some of the persistent neurobehavioural consequences of repeated exposure to psychostimulant drugs may be due to their ability to reorganize patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex.

A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat ☆

This experiment examines the notion that in the rat the hippocampal formation is an essential structure in the neurological representation of spatial abilities. Spatial localization by rats with different types of hippocampal damage, including bilateral electrolytic lesions, unilateral and bilateral kainic acid-induced CA3-CA4 lesions, and unilateral and bilateral colchicine-induced dentate gyrus lesions, was compared with vehicle-injected and normal control groups in the Morris water task. The task required the rats to escape from cold water by finding a submerged and hidden platform located at a fixed place within the room. The start point was varied randomly from trial to trial and there were no local cues available to indicate the position of the hidden platform. After training, the platform was moved. Escape latencies and the initial swimming headings revealed that all lesion groups, except the unilateral CA3-damaged group, were impaired at finding the platform: the dentate-damaged rats exhibited the greatest deficit. When the platform was moved the control rats swam mainly in the part of the pool that had previously contained the platform and, on finding it in the new location, they showed a marked dishabituation of rearing. None of the bilateral lesion groups showed these effects.

Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat

Abstract Unlike normal rats, rats with bilateral lesions in either the hippocampus or medial frontal cortex did not learn to swim from different directions to a hidden platform located at a specific place in a room. Experimental and clinical evidence indicates that a fronto-hippocampal system may provide an integrated neurological basis for spatial representational ability.

A method for vibratome sectioning of Golgi-Cox stained whole rat brain.

A method for impregnating the whole rat brain with Golgi-Cox stain and sectioning with the vibratome is described. The method is simple, inexpensive and provides good resolution of dendrites and spines.

Performance of Schizophrenic Patients on Tests Sensitive To Left or Right Frontal, Temporal, or Parietal Function in Neurological Patients

The performances of schizophrenic patients and normal control subjects were compared on an extensive battery of psychological tests that have been found at the Montreal Neurological Hospital to be differentially sensitive to atrophic lesions of the left or right frontal, temporal, or parietal cortex. Schizophrenic patients were significantly impaired at all tests that are disrupted by left or right frontal or temporal lobe lesions but performed within normal limits on all tests that are sensitive to parietal lobe damage. These results imply that schizophrenia results, at least in part, from a bilateral dysfunction of the frontal and temporal lobes.

Harnessing neuroplasticity for clinical applications

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

A comparison of the contributions of the frontal and parietal association cortex to spatial localization in rats.

Rats with lesions of the medial frontal, orbital frontal, or parietal cortex were compared behaviorally with rats with complete removal of the neocortex and normal control rats on three spatial tasks: Morris water task, radial arm maze, and spatial reversals in a Grice box. Decortication produced severe impairments in the acquisition of all three tasks, thus providing a measure against which to compare the severity of the impairments observed following more restricted removals. Rats with parietal cortex lesions were relatively unimpaired at any of the tasks, although they had a significant deficit on the spatial reversal task and had a short-term memory impairment on the radial arm maze. In contrast, rats with medial frontal lesions had a significant, but relatively mild, impairment on the radial arm maze and were very poor at learning the water task. Rats with orbital frontal lesions were nearly as impaired on the radial arm maze and water task as decorticate rats. The results suggest that the frontal and parietal cortex of rats play different roles in the control of spatial orientation but do not support the view that egocentric and allocentric spatial orientation are related to frontal and parietal mechanisms, respectively. In addition, the results suggest that the frontal cortex plays a larger role in the control of spatially guided behavior than has been previously recognized and that both the medial frontal and the orbital (sulcal) frontal cortex play a dissociable role in the control of spatial orientation.